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Original Investigation
November 19, 2020

Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer: A Phase 2 Nonrandomized Clinical Trial

Author Affiliations
  • 1Department of Gynecologic Oncology, Clinical Sciences Center, Roswell Park Comprehensive Cancer Center, Buffalo, New York
  • 2Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York
  • 3Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
JAMA Oncol. 2021;7(1):78-85. doi:10.1001/jamaoncol.2020.5945
Key Points

Question  Is the activity of immune checkpoint inhibitors augmented by combination therapy with bevacizumab and metronomic cyclophosphamide in patients with recurrent ovarian cancer?

Findings  In this single-arm, phase 2 nonrandomized clinical trial, 40 patients with platinum-sensitive or platinum-resistant ovarian cancer received pembrolizumab with bevacizumab every 3 weeks and oral cyclophosphamide daily. The objective response rate was 47.5% with a median progression-free survival of 10.0 months, and this regimen was well tolerated with good quality of life during treatment.

Meaning  These findings suggest that the combination of pembrolizumab with bevacizumab and metronomic cyclophosphamide has clinical activity with a favorable toxicity profile in treatment of recurrent ovarian cancer.

Abstract

Importance  Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies.

Objective  To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Design, Setting, and Participants  This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020.

Interventions  Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent.

Main Outcomes and Measures  Primary outcomes were objective response rate (ORR) and progression-free survival (PFS).

Results  Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]).

Conclusions and Relevance  In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer.

Trial Registration  ClinicalTrials.gov Identifier: NCT02853318

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